AMR 2: Management of Antimicrobial resistant gram negatives

AMR 2: Management of Amp-C Enterobacterales, Carbapenem resistant Acinetobacter baumannii, Stenotrophmonas maltophilia

The second part to the IDSA Guidance paper on the management of antibiotic resistant gram negative bacteria is out. AMR 1 focused on the management of ESBL Enterobacterales, Carbapenem Resistant Enterobacterales and DTR Pseudomonas aeruginosa, click here for my prior review and here for the wonderful tables I made.

AMR 2 is a welcome addition to the IDSA’s guidance paper series. These are living documents that will be edited and changed frequently to keep them as updated as possible. AMR 2 focuses on Amp-C, CRAB and Stenotrophomonas. The initial sections of the document are identical to AMR 1 and focus on empiric management and when to alter empiric therapy. Also, there is a discussion of duration and how resistance does not affect the duration of therapy. Again, click here for my review and AMR 1. Now to the meat of the guidance paper.

Amp-C Enterobacterales: Say goodbye to SPICE or SPICE-M

3 mechanisms:

• Inducible, chromosomal
• Stable chromosomal de-repression
• Plasmid mediated Amp-C

Inducible, chromosomal: usually after a few doses of ceftriaxone (CRO) or ceftazidime (CAZ). Over expression, and the greatest concern for activation, is seen with Enterobacter cloacae, Klebsiella aerogenes and Citrobacter freundii. Low level activation is seen in Providencia spp, Morganella morganii and Serratia marcescens. Unknown activity is seen in Hafnia alvei, Citrobacter youngae and Yersinia enterocolitica. So, you are wondering what about the SPICE-M bacteria, apparently this is old news (and totally news to me). The prior SPICE-M (Serratia, Proteus (Indole positive), Citrobacter, Enterobacter, Morganella), well some are still there, but some are not or have changed their name. The indole-positive Proteus that had inducible Amp-C are now Providencia and Morganella; P vulgaris and P penneri do not have inducible Amp-C.

De-repressed Chromosomal: E. coli and Shigella. These organisms have a promoter mutation or attenuation of the Amp-C or a regulator gene that alters, but does not stop, production.

Plasmid: seen in E coli, K pneumoniae and Salmonella.

#1: Which Enterobacterales are at high risk for Amp-C production

For the high-risk organisms, E cloacae, K aerogenes and C freundii, preferred treatment is cefepime. For the other possible Amp-C producers, treatment based in susceptibilities is appropriate.

#2: What features should be considered in selecting antibiotics for infections caused by organisms with moderate to high risk of clinically significant AmpC production due to an inducible ampC Gene?

Multiple antibiotics can induce the Amp-C gene, but some are not hydrolyzed by this enzyme. This means that even though they can turn the gene on, they remain active against the bacteria. Those that induce the Amp-C and are hydrolyzed are inactive against the organism.

Antibiotics that affect Amp-C production
Antibiotic	Inducer	Hydrolyzed
Aminopenicillins	+	+
1st Gen Cephalosporins	+	+
Cephamycins (cefoxitin)	+	+
Imipenem	+	θ
Ertapenem	?	θ
Meropenem	?	θ
Piperacillin	+	+
Ceftriaxone	+	+
Ceftazidime	+	+
Aztreonam	+	+
Cefepime	+(mild)	θ

#3: Role of cefepime in the treatment of high-risk Amp-C

Cefepime is the preferred treatment for the high-risk Amp-C producing bacteria. If the MIC is </=2 mcg/ml use cefepime, for MIC >/=4 mcg/ml use a carbapenem. High cefepime MICs indicate the presence of an ESBL or other resistance mechanism.

#4: Role of CRO or CAZ in the treatment of high-risk Amp-C

CRO and CAZ are not recommended for the treatment of high-risk organisms with Amp-C. It may be reasonable to use CRO or CAZ for the treatment of cystitis.

#5: Role of piperacillin-tazobactam

Not recommended

#6: Role of new antibacterials

These should be reserved for CRE, DTR Pseudomonas and other difficult to treat organisms

#7: Role of non-b-lactam antibacterials (FQ and TMP-SMX)

If the organism is susceptible to a FQ or TMP-SMX, these agents can be used as treatment. For cystitis nitrofurantoin can be used, if the organism is susceptible.

Carbapenem Resistant Acinetobacter baumannii (CRAB)

Carbapenem resistant in mediated by serine and metallo-b lactamases, OXA-24/40 and OXA-23 carbapenemases and sulbactam resistance is mediated by Penicillin-binding Proteins (PBPs).

#1: General approach to the treatment of CRAB

Mild infections can be treated with a single agent. Typically, whatever the organism is susceptible to can be used. Preference is given to amp-sulbactam followed by minocycline, polymyxin B, tigecycline or cefiderocol. For more severe infections 2-3 agents should be used. The guidance group recommends high dose amp-sulbactam (even if resistant) paired with minocycline/tigecycline/polymyxin. Cefiderocol or continuous infusion meropenem can be added, but may have higher toxicity with duel b-lactam therapy

#2: For moderate-severe infections, use combination therapy

At least 2 agents should be given. High-dose Ampicillin-sulbactam (9 g IV q8h over 4 hours  OR  27 g IV q24h as a continuous infusion) paired with teracycline, polymyxin, extended infusion meropenem or cefiderocol.

#3-9: Re-enforces the use of ampicillin-sulbactam, second agents should be tetracyclines or polymyxin. Can add extended infusion meropenem or cefiderocol when there is no other agents available, as add on agents. The group recommends against the use of inhaled antibiotics.

Stenotrophomonas maltophilia

This organism likes to form biofilms, takes advantage of hospitalized or immune compromised hosts and it is often difficult to distinguish between infection and colonization. Stenotrophomonas is resistant to many antibacterials. It has 2 different b-lactamases; L1 (a metallo-b-lactamase) that confers resistance to penicillins, cephalosporins and carbapenems, but not aztreonam; L2 (a serine-b-lactamase) that has extended cephalosporin activity and activity against aztreonam. It has intrinsic resistance to aminoglycosides. It has efflux pumps (resistance to tetracyclines and FQ) and the SMgnr gene (that interferes with FQ binding to gyrase and topoisomerase).

#1: General approach to treatment of Stenotrophomonas

Mild infections can be treated with TMP-SMX, minocycline, levofloxacin or cefiderocol. CAZ should be avoided due to the multiple resistant mechanisms (even when susceptible, as resistance develops on therapy). Moderate to severe infections should be treated 1) TMP-SMX plus minocycline; 2) TMP-SMX and add a second agent of no improvement; 3) ceftazidime-avibactam plus aztreonam.

#2-6: Review the data for each antibacterial. High light is to avoid FQ therapy, resistance develops while on therapy due to the Smgnr mutation. Avoid CAZ due to high likelihood of developing resistance while on therapy.

So, bottom line for treating:

• Amp-C producer: use cefepime, TMP-SMX or FQ
• CRAB:
  1. Mild infection: Monotherapy with amp-sulbactam preferred. Can use minocycline or polymyxin
  2. Mod-severe: combination of 2 or more agents. Should have amp-sulbactam and then add agents. Amp-Sulbactam should be high-dose, 9 g IV q8h over 4 hours OR 27 g IV q24h as a continuous infusion. Can also use high dose meropenem + polymyxin + AS or minocycline
• Stenotrophomonas:
  1. Mild infection can treat with monotherapy with TMP-SMX, minocycline or FQ
  2. Severe infection use 1) TMP-SMX + minocycline; 2) TMP-SMX and add if no improvement; 3) CAZ/avibactam + aztreonam

See Table in Quick Bites